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Gi/Pulmonary EXAM 1 - Neumann Arth/Gout
GI/Pulmonary EXAM 1 - Neumann Arth/Gout
77
Pharmacology
Graduate
03/21/2011

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Term
all-trans ring fusion
Definition
what is the stereochemistry of nearly all important corticosteroids?
Term
[image]
Definition
in steroids with all-trans ring fusions, the rings are conformationally locked in chair formations.

there are 2 surfaces to the rigid all trans system: the top side ( ) and the bottom side ( )
Term
all cellular responses to glucocorticoids are attributed to their binding to the intracellular glucocorticoid receptor, translocation to the nucleus followed by dimerization and modulation of gene expression

desired cellular responses are:

anti-inflammatory
immunosuppressive: lowers lymphocyte numbers, alteration of their responses

repression of:
NF-kB
IL-1
IL-6
TNFa

synthesis of annexin-1: inhibitor of PLA2 (causes release of arachidonic acid) leading to downregulation of prostaglandins

down-regulates COX2 expression
Definition
MOA of glucocorticoids
Term
increases gluconeogenesis
increases glycogenesis
increases protein catabolism
decreases antibody response
anti-inflammatory response

ex) cortisol
Definition
functions of glucocorticoids
Term
cortisol
Definition
[image]
Term
increase Na and water retention
promote K loss

ex) aldosterone
Definition
function of mineralocorticoids
Term
aldosterone
Definition
[image]
Term
hydrocortisone
cortisone
Definition
short acting glucocorticoids
Term
11B-HSD1: liver enzyme that reversibly interconverts hydrocortisone to cortisone (inactive metabolite; serves as a storage depot)

11B-HSD2: kidney enzyme that irreversibly converts hydrocortisone to cortisone; prevents hydrocortisone from binding to mineralocorticoid receptors preventing some kidney issues
Definition
metabolism of hydrocortisone
Term
both GR and MR activity
Definition
activity of hydrocortisone
Term
[image]

urocortisol is the major metabolite (along with its conjugates) and has the 5-beta configuration - give a cis-A/B ring fusion that is inactive
Definition
illustration of hydrocortisone metabolism
Term
fludrocortisone
Definition
[image]
Term
11X as potent as hydrocortisone in RA

MR activity increased 300-800 times!

intense Na retaining activity
Definition
activity of fludrocortisone
Term
[image]
Definition
the delta-1 corticoids
Term
more potent antirheumatic and antiallergenic agents than cortisol derivatives

prednisone and prednisolone are 3-4x more potent anti-inflammatories than hydrocortisone but their mineralocorticoid activity was not proportionally increased
Definition
activity of prednisone and prednisolone
Term
prednisone
prednisolone
methylprednisolone
triamcinolone
Definition
intermediate acting glucocorticoids
Term
prednisone and prednisolone are interconvertable by 11B-HSD in the liver

equipotent and can be used interchangably

prednisone is metabolized to a number of hydrophilic and less active metabolites

MAJOR METABOLITES: 6B- and 16a-hydroxy are excreted as glucuronide conjugates in urine
Definition
metabolism of prednisone and prednisolone
Term
[image]
Definition
evolution of the delta-1 corticoids
Term
[image]
Definition
illustration of prednisone metabolism
Term
methylprednisolone
Definition
[image]
Term
extensive: 10% recovered unchanged in the urine

[image]

reduction of C20 ketone
oxidation of 17B-ketol group to the C21 acid and the C20 etio acid
6B-hydroxylation by CYP3A4

CYP3A4 inhibitors such as antifungals, ketoconazole, itraconazole can potentiate the effects of MP
Definition
metabolism of methylprednisolone
Term
~20% more potent than prednisolone
Definition
activity of methylprednisolone
Term
triamcinolone

may actually cause Na excretion

other side effects: anorexia, muscle weakness, leg cramps, nausea, dizziness, and a general toxic feeling
Definition
[image]
Term
[image]

6B-hydroxylation through CYP3A4
Definition
metabolism of triamcinolone
Term
~20% more potent than prednisone
Definition
activity of triamcinolone
Term
16-methyl corticoids:

dexamethasone and betamethasone
Definition
long acting glucocorticoid
Term
dexamethasone: a 16-methyl corticoid

like 16a-OH, the methyl greatly reduces salt retaining properties (MR)
Definition
[image]
Term
similar to prednisone, 6B-hydroxy major metabolite in urine
Definition
metabolism of dexamethasone
Term
30X potency of hydrocortisone
5X potency of prednisone

Dex-21-phosphate for IV
Definition
activity of dexamethasone
Term
betamethasone: a 16-methyl corticoid
Definition
[image]
Term
similar to methylprednisone and prednisone
Definition
metabolism of betamethasone
Term
slightly more active than dexamethasone

overall very similar
Definition
activity of betamethasone
Term
all trans B/C and C/D is necessary for activity

[image]

suggested that beta surface of C/D and 17B-ketol are most important for association with GR

generally, bulky beta-substituents abolish GR activity whereas alpha-side does not

[image]

17a-CH3, 16a-CH3, 16B-CH3, 16a-CH3O, 16a-OH reverse or even abolish Na retaining activity (MR activity)

[image]

[image]

inserting a-CH3 at position 2, 6, 16 in 11B-OH compounds improves GR activity
2a-CH3 prevents metabolic reduction of the double bond

[image]

alkyl substitution at 4, 7a, 9a, 11a, and 21 decrease activity

most of the time need 11B-OH for activity

9a-F group increases GR/MR activity and nearly prevents metabolic oxidation of 11B-OH (increases acidity of OH - better H-bond donor to GR)
Definition
summary of glucocorticoid SAR
Term
1) anti-inflammtory:
decrease in vasodilator prostaglandins (PGE2, PGI2) affords less vasodilation and therefore less edema
prostaglandins enhance leukocyte infiltration by promoting blood flow

2) analgesic:
decreased in prostaglandins generation affords less sensitization of nociceptive nerve endings to bradykinin and 5-HT
also, prostaglandins are part of the neuroimmune activation response of glial cells
3) antipyretic:
decrease in mediator prostaglandin (generated in response to IL-1) that is responsible for elevating the hypothalamic set-point for temperature control in fever
Definition
NSAIDs have 3 major actions resulting from inhibition of COX (and thus decreasing prostaglandin formation):
Term
arachidonate is stored in cell membranes esterified at glycerol C2 of phosphatidyl-inositol and other phospholipids

[image]

cleavage is mediated by phospholipase A2

corticosteroids are anti-inflammatory agents because they inhibit (indirectly) PLA2, reducing the rate of arachidonic acid production
Definition
storage and mobilization of arachidonic acid and corticosteroid's role in this process
Term
[image]

COX activity:
COX has an iron center; usually Fe-4 and is activated to Fe-5
the iron center of COX forms a radical from tyrosine
radical tyrosine produces an allylic shift and a cycle is formed
proton is returned to tyrosine
end result is PGG2

peroxidase activity:
hydroperoxide converted to an alcohol

different prostaglandins will be formed depending on the tissue
Definition
mechanism of prostaglandin formation
Term
COX2
Definition
the prostaglandins derived from this COX are found mainly at sites of inflammation and are thought to trigger and/or exacerbate the inflammation process

expression is induced by: IL-1, IL-2, TNFa, and growth factors

expression is repressed by: IL-4 and IL-10, IL-13, glucocorticoids
Term
COX1 is 67% identical to COX2 with respect to primary amino acid sequences

COX1 has isoleucine in the active site
COX2 has valine in this position

[image]

the difference of a single methyl group (between valine and isoleucine) gives raise to COX1 having a 25% smaller pocket than COX2

the side-pocket feature of COX2 has be exploited to afford selective inhibitors
Definition
differences between COX1 and COX2 binding sites
Term
salicylates inhibits both COX1 and COX2, but are more selective for COX1

most are reversible inhibitors (except for aspirin - acetyl salicylic acid)

also inhibit platelet activation
Definition
MOA of salicylates

[image]
Term
[image]
Definition
metabolism of aspirin
Term
aspirin covalently and irreversibly modifies both COX1 and COX2 by acetylating serine-530 in the active site

[image]

acetylation of COX1 blocks entrance of arachidonic acid to active site
acetylation of COX2 retains some COX and peroxidase activity

acetylated COX2 gives raise to aspirin-triggered lipoxin: anti-inflammatory agent, protect endothelial cells, resolves inflammation

[image]
Definition
MOA of aspirin
Term
[image]
Definition
general SAR of arylalkanoic acids (largest group of NSAIDs)
Term
[image]
Definition
indole, indene acetic acids
Term
[image]

converted to inactive metabolites
50% is 5-O-demethylated by CYP2C9
10% glucuronidated in liver
non-hepatic enzyme systems N-deacylate indomethacin
Definition
metabolism of indomethacin

[image]
Term
[image]

prodrug: sulindac is absorbed as sulfoxide which is not a COX inhibitor (solubility)

thus no inhibition of prostaglandins in GI tract - fewer side effects

reduces sulfide in blood

active metabolite has 2X t1/2 of parent

overall side effects are less than indomethacin but still see some irritation of the GI tract

longer term uses
Definition
metabolism of sulindac

[image]
Term

[image]

extensive 1st pass metabolism

excreted in urine

less active than indomethacin

metabolized by oxidation of methyl to alcohol and then acid (conjugation)

 

[image]

very potent

metabolized by CYP2C9 p-hydroxy derivative and then to conjugates excreted in urine

Definition
heteroaryl acetic acids
Term
diclofenac

[image]

structural characteristics of both arylalkanoic acid and anthanilic acid (benzyl-N) classes

2x the potency of indomethacin and 450x the potency of aspirin for anti-inflammatory
6x the potency of indomethacin and 40x the potency of aspirin as an analgesic
2x the potency of indomethacin and >350x the potency of aspirin as an antipyretic
Definition
[image]
Term
1) inhibition of COX enzymes - decreased prostaglandins and thromboxanes

2) inhibition of the lipoxygenase pathway - decreased leukotrienes (LTB4)

3) inhibition of arachidonic acid release and stimulation of its reuptake
Definition
unique 3-fold MOA of diclofenac
Term
[image]

major metabolite via CYP3A4 is 4'-hydroxy: para orientation in an aromatic ring is BAD = liver toxicity!

other metabolites through CYP2C9

remaining drug is excreted as sulfate conjugates

[image]

glutathione can neutralize the reactive metabolite
Definition
metabolism of diclofenac

[image]
Term
[image]

[image]
Definition
propionic acid derivatives
Term
marketed as a racemate but S-(+) is active isomer

more potent than aspirin but less than indomethacin

a-methyl group increases activity and decreases toxicity
Definition
activity of ibuprofen (propionic acid derivative)
Term
12X potency of aspirin, 3-4x potency of ibuprofen inhibiting PGH2 production

300X less potent than indomethacin

[image]

SAR - 6 substitution gives optimal anti-inflammatory activity (CH3O was most potent)
Definition
activity of naproxen
Term
60% eliminated unchanged

10% as unchanged conjugates

remainder de-methylated by CYP3A4 and CYP1A2 then to glucuronide
Definition
metabolism of naproxen

[image]
Term
[image]

when administered as a racemate or individual enantiomers, the major metabolite isolated is always S-(+)

[image]

R-(-) enantiomer is epimerized to the S-(+) in vivo via a acetyl-CoA intermediate - thus the 2 enantiomers are bioequivalent
Definition
metabolism of ibuprofen

[image]
Term
oxaprozin

anti-inflammatory with rapid onset of action and prolonged duration of action (equipotent with aspirin)
Definition
[image]
Term
little first pass metabolism

5% excreted unchanged

microsomal oxidation (CYP2C9)
glucuronidation
ester conjugation
small amounts of phenol metabolites
Definition
metabolism of oxaprozin

[image]
Term
flurbiprofen

most potent derivative of a series of phenyl alkanoic acids

first marketed as the 1st topical NSAIDs for ophthalmic use

536x potency of aspirin in inflammation
0.5x potency of methylprednisolone
403x potency of aspirin as an analgesic
26x potency of ibuprofen as an analgesic
Definition
[image]
Term
[image]
Definition
metabolism of flurbiprofen

[image]
Term
[image]
Definition
SAR of N-arylanthranilic acids: fenamates
Term
[image]

meclofenamate:
[image]
Definition
example of an N-arylanththranilic acid
Term
[image]

metabolism by CYP2C9

50-55% renal (gluc)
Definition
metabolism of mefenamic acid
Term
piroxicam:
[image]

meloxicam:
[image]
Definition
examples of enolic acids: the "oxicams"
Term
non-carboxylic acid anti-inflammatory

[image]
Definition
SAR of enolic acids: the "oxicams"
Term
[image]
Definition
metabolism of piroxicam

[image]
Term
[image]
Definition
activity and metabolism of meloxicam
Term
considered a COX2 selective inhibitor

[image]
Definition
activity of celecoxib
Term
CYP2C9 hydroxylation of 4-methyl group

[image]

metabolites do not inhibit COX1 or COX2
celecoxib also inhibits CYP2D6

may increase risk of serious cardiovascular thrombotic events
suppression of PGI2 may result in elevated BP and atherogenesis with heightened thrombotic response to plaque ruptures
suppresses prostaglandins (vasodilator) but do not inhibit platelet action = CV events
Definition
metabolism of celecoxib

[image]
Term
[image]
Definition
other COX2 inhibitors
Term
nabumetone

new class of non-acidic NSAID prodrugs
since non-acidic it does not produce a significant "primary insult"
it is also not an inhibitor of COX in the GI mucosa so produced a minimal "secondary insult"

13x anti-inflammatory potency of aspirin
Definition
[image]
Term
[image]
Definition
metabolism of nabumetone

[image]
Term
causes decreased PGE2 levels in CNS (where COX3 is found)
no ulcerogenic activity like aspirin or other NSAIDs
acetaminophen is only effective when COX2 is at low levels

inhibits the activation of COX2 by inhibiting oxidation of the central iron from Fe4 to Fe5
Definition
MOA of acetaminophen

[image]
Term
[image]

[image]

rapid first pass metabolism primarily by conjugation

CYP2E1 leads to small amount but significant N-OH and then to the quinone

normally, immediate detox by glutathione takes place

overdoses leads to S-mediated addition of hepatic proteins

N-acetylcysteine used as a rescue (mucomyst)
Definition
metabolism of acetaminophen
Term
methotrexate

rate limiting enzyme of TMP synthesis is thymidylate synthase

methotrexate inhibits DHFR causing levels of 7,8-dihydrofolate to build up

high levels of 7,8-dihydrofolate causes feedback inhibition of thymidylate synthase and pyrimidine synthesis cannot occur

[image]
Definition
[image]
Term
[image]

methotrexate is actively transported into the urine

probenacid, NSAIDs, penicillin G produce life-threatening drug interactions with methotrexate

dose-dependent inhibition of OATs
Definition
metabolism of methotrexate
Term
DMARD: anti-inflammatory, immunosuppressant

well-absorbed - PRODRUG
[image]

exact MOA unknown but involves B-cell proliferation

[image]
Definition
MOA of leflunomide

[image]
Term
5-10% excreted unchanged

glucuronide conjugation

omega-oxidation of propyl: oxidation of resulting alcohol to acid

omega-1-oxidation of propyl

N-dealkylation
Definition
metabolism of probenecid

[image]

enhances excretion of urate through inhibition of URAT1
Term
substrate of XO with 15-20x the affinity of xanthine and reversibly inhibits the enzyme

rapidly metabolized via oxidation - forms numerous ribonucleoside derivatives

oxypurinol is major metabolite - also inhibits XO

[image]

drug interaction with 6-mercaptopurine
Definition
MOA of allopurinol

[image]
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